Arylopeptoid oligomers functionalised by combinatorial or sequential on-resin click chemistry using a copper(I)-N-heterocyclic carbene catalyst.

An efficient on-resin click chemistry protocol using a stable copper(I)-N-heterocyclic carbene catalyst is developed for post-functionalization of N-alkylated aminomethylbenzamide oligomers (arylopeptoids). The accessibility to a panel of polyfunctionalized N-substituted aromatic oligoamides by solid-phase synthesis is demonstrated using combinatorial and sequential approaches.

NCα-gem-dimethylated peptoid side chains: A novel approach for structural control and peptide sequence mimetics.

The design of linear peptoid oligomers adopting well-defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis-inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα-gem-dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block-coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα-gem-dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα-gem-dimethyl side chains relative to the peptoid backbone.

Exploring the Conformation of Mixed Cis- Trans α,ß-Oligopeptoids: A Joint Experimental and Computational Study.

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,ß-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-ß- trans-α, cis-α- trans-ß, trans-ß- cis-α, and trans-α- cis-ß. α- and ß NtBu monomers were used to enforce cis-amide bond geometries and α- and ß NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-ß and cis-ß- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-ß and trans-ß- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-ß-based oligomers. Interestingly, the trans-α- cis-ß peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains.

Peptoids that are oligomers of N-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the cis and trans conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-cis polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (n → π*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1-naphthylethyl (1npe) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered α-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (S)-N-(1-tert-butylethyl)glycine (Ns1tbe) peptoid homo-oligomers. The X-ray crystal structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only α-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of NtBu and Ns1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(tBu)2-(s1tbe)4-(tBu)2-COOtBu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence.

1,2,3-Triazolium-Based Peptoid Oligomers.

The cis-directing effect of the 1,2,3-triazolium-type side chain was studied on dimeric peptoid models with various patterns: αα, αß, ßα and ßß. Low influences of the sequence and of the solvent were observed, the cis conformation of the amide carrying the triazolium ranging from 83 to 94% in proportion. The synthesis of peptoid homooligomers with four or eight pendant 1,2,3-triazolium side chains is described. α-, ß- and α,ß-peptoids carrying propargyl groups were subjected to CuAAC reaction using alkyl azides, and the resulting triazoles were quaternized providing well-defined multitriazolium platforms. The influence of the counteranion (PF6-, BF4- or I-) on the conformation was also studied.

Design of Triazolium-Grafted Peptidomimetic Macrocycles with Facial Amphipathicity to Target Pathogenic Bacteria.

Access to 1,2,3-triazolium-grafted peptoid macrocycles was developed by macrocyclization and multivalent postmodification of linear peptoid oligomers carrying an alternance of benzylic and propargyl groups as side chains. X-ray analysis and NMR studies revealed a conformational preference for constrained hairpin-shaped structures leading to the facial amphipathic character of these macrocycles. A preliminary evaluation showed the antimicrobial activities of these new cationic amphipathic architectures.

Cage-like structures based on constrained cyclic arylopeptoids.

The access to cupola-like or tube-like structures from ortho- and meta-arylopeptoid macrocycles was explored through CuAAC reaction using a partially flexible bis(azide) and CuI-N-heterocyclic carbene as catalyst. NMR studies showed that a bis-triazolium bicylic compound in the ortho-series adopts well-defined structure in polar aprotic and protic solvents. Besides, preliminary study revealed its potential for oxoanion recognition.

Pharmacological and structural characterization of conformationally restricted (S)-glutamate analogues at ionotropic glutamate receptors.

Conformationally restricted glutamate analogues have been pharmacologically characterized at AMPA and kainate receptors and the crystal structures have been solved of the ligand (2S,1'R,2'S)-2-(2'-carboxycyclobutyl)glycine (CBG-IV) in complex with the ligand binding domains of the AMPA receptor GluA2 and the kainate receptor GluK3. These structures show that CBG-IV interacts with the binding pocket in the same way as (S)-glutamate. The binding affinities reveal that CBG-IV has high affinity at the AMPA and kainate receptor subtypes. Appreciable binding affinity of CBG-IV was not observed at NMDA receptors, where the introduction of the carbocyclic ring is expected to lead to a steric clash with binding site residues. CBG-IV was demonstrated to be an agonist at both GluA2 and the kainate receptor GluK1. CBG-IV showed high affinity binding to GluK1 compared to GluA2, GluK2 and GluK3, which exhibited lower affinity for CBG-IV. The structure of GluA2 LBD and GluK3 LBD in complex with CBG-IV revealed similar binding site interactions to those of (S)-glutamate. No major conformational rearrangements compared to the (S)-glutamate bound conformation were found in GluK3 in order to accommodate CBG-IV, in contrast with GluA2 where a shift in lobe D2 binding site residues occurs, leading to an increased binding cavity volume compared to the (S)-glutamate bound structure.

The click triazolium peptoid side chain: a strong cis-amide inducer enabling chemical diversity.

Access to homogeneous and discrete folded peptoid structures primarily depends on control of the cis/trans isomerism of backbone tertiary amides. This can be achieved by designing specific side chains capable of forming local interactions with the backbone. This is often undertaken at the expense of side-chain diversity, which is a key advantage of peptoids over other families of peptidomimetics. We report for the first time a positively charged triazolium-type side chain that does not compromise diversity and exhibits the best ability reported to date for inducing the cis conformation. The cis-directing effect was studied in N-acetamide dipeptoid model systems and evaluated in terms of K(cis/trans) using NMR spectroscopy in aprotic and protic solvents. Computational geometry optimization and natural bond orbital analysis in combination with NOESY experiments were consistent with a model in which n → π*(Ar) electronic delocalization [from carbonyl (O(i-1)) to the antibonding orbital (π*) of the triazolium motif on residue i] may be operative. In the computational model (gas-phase) and experimentally in CDCl(3), H-bonding between the triazolium C-H proton and the C(i)═O(i) oxygen was also identified and may act cooperatively with the n → π*(Ar) delocalization, resulting in the absence of the trans rotamers in CDCl(3).

Selectivity among two lectins: probing the effect of topology, multivalency and flexibility of "clicked" multivalent glycoclusters.

The design of multivalent glycoconjugates has been developed over the past decades to obtain high-affinity ligands for lectin receptors. While multivalency frequently increases the affinity of a ligand for its lectin through the so-called "glycoside cluster effect", the binding profiles towards different lectins have been much less investigated. We have designed a series of multivalent galactosylated glycoconjugates and studied their binding properties towards two lectins, from plant and bacterial origins, to determine their potential selectivity. The synthesis was achieved through copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) under microwave activation between propargylated multivalent scaffolds and an azido-functionalised carbohydrate derivative. The interactions of two galactose-binding lectins from Pseudomonas aeruginosa (PA-IL) and Erythrina cristagalli (ECA) with the synthesized glycoclusters were studied by hemagglutination inhibition assays (HIA), surface plasmon resonance (SPR) and isothermal titration microcalorimetry (ITC). The results obtained illustrate the influence of the scaffold's geometry on the affinity towards the lectin and also on the relative potency in comparison with a monovalent galactoside reference probe.

Cyclic α,ß-peptoid octamers with differing side chain patterns: synthesis and conformational investigation.

The solution-phase synthesis and cyclisation of three α,ß-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,ß-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the ß-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.

Efficient and versatile COMU-mediated solid-phase submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides).

The development of a highly efficient methodology for solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) with free acids or free amides at the C-terminus is described. The arylopeptoids were synthesised by means of a convenient submonomer protocol in which the arylopeptoid residues were created in an iterative manner on the growing chain using an acylation-substitution cycle. The uronium salt COMU was found to be the most efficient reagent for ensuring fast and clean couplings of the benzoic acid building blocks.

N-Alkylated Aromatic Poly- and Oligoamides.

N-alkylated aromatic poly- and oligoamides are a particular class of abiotic foldamers that is deprived of the capability of forming intramolecular hydrogen-bonding networks to stabilize their tri-dimensional structure. The alkylation of the backbone amide nitrogen atoms greatly increases the chemical diversity accessible for aromatic poly- and oligoamides. However, the nature and the conformational preferences of the N,N-disubstituted amides profoundly modify the folding properties of these aromatic poly- and oligoamides. In this Review, representative members of this class of aromatic poly- and oligoamides will be highlighted, among them N-alkylated phenylene terephthalamides, benzanilides, pyridylamides, and aminomethyl benzamide oligomers. The principal synthetic pathways to the main classes of N-alkylated aromatic polyamides with narrow to broad molecular-weight distribution, or oligoamides with specific sequences, will be detailed and their foldameric properties will be discussed. The Review will end by describing the few applications reported to date and future prospects for the field.

Expedient preparation of all isomers of 2-aminocyclobutanecarboxylic acid in enantiomerically pure form.

A short, convenient, gram scale protocol has been established to allow facile access to all four stereoisomers of 2-aminocyclobutanecarboxylic acid, each in enantiomerically pure form (ee >99%). Starting from the readily available cis racemate, the procedure combines efficient alpha-phenylethylamine derivative resolution and controlled cis-to-trans epimerization procedures, and proceeds with invariably high yields.

Cyclic beta-peptoids.

The first synthesis of functionalized beta-peptoid macrocycles is reported. X-ray crystallographic structure of tetramer 9 reveals a C2-symmetrical derivative with unexpected all-cis-amide bonds and spatial disposition of the appendages toward the two opposite faces of the ring. Quantum calculations suggest that 9 is locked in this layout. These macrocycles constitute novel promising templates for multimeric ligation of biologically active ligands. The concept was exemplified by chemical decoration of tetramer 9 via "click" reactions.

Rapid assembly of the polyhydroxylated beta-amino acid constituents of microsclerodermins C, D, and E.

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated beta-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.

Topologically Diverse Shapes Accessible by Modular Design of Arylopeptoid Macrocycles.

N-Substituted aromatic cyclooligoamides composed of different combinations of ortho-, meta-, and/or para-arylopeptoid residues carrying methoxyethyl side chains have been efficiently synthesized by macrocyclization of the corresponding linear oligomers. The study of the architectures of these macrocycles in solution and solid state has revealed that tetracyclic arylopeptoids adopt sequence-dependent shapes with different backbone amide conformations and side-chain orientations. Remarkably, despite the absence of intramolecular H-bonding ability, some of these arylopeptoid macrocycles show well-defined architectures in solution.

1,2,3-Triazolium-Based Cationic Amphipathic Peptoid Oligomers Mimicking Antimicrobial Helical Peptides.

Amphipathic cationic peptoids (N-substituted glycine oligomers) represent a promising class of antimicrobial peptide mimics. The aim of this study is to explore the potential of the triazolium group as a cationic moiety and helix inducer to develop potent antimicrobial helical peptoids. Herein we report the first solid-phase synthesis of peptoid oligomers incorporating 1,2,3-triazolium-type side chains and their evaluation against Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus. Several triazolium-based oligomers, even of short length, selectively kill bacteria over mammalian cells. SEM visualization of S. aureus cells treated with a dodecamer and a hexamer reveals severe cell membrane damage and suggests that the longer oligomer acts by pore formation.

Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3.

The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine, l-CBG-I, l-CBG-II, l-CBG-III, and l-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2-oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, l-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, l-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas l-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer l-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.